Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Abstract

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID‐19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV‐ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC‐CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug‐induced CV‐ADRs from COVID‐19 effects, we restricted analyses to patients with COVID‐19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08–3.29), bradycardia (aOR: 2.09, 95% CI: 1.24–3.53), and hypotension (aOR: 1.67, 95% CI: 1.03–2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC‐CMs in time‐ and dose‐dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.

Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes

“…VigiBase is an individual case safety report database of the World Health Organization (WHO) evaluated by a group of scientists from Seoul, Korea [ 103 ]. Cardiac arrest (adjusted odds ratio (aOR): 1.88, 95% confidence interval (CI): 1.08–3.29), bradycardia (aOR: 2.09, 95% CI: 1.24–3.53), and hypotension (aOR: 1.67, 95% CI: 1.03–2.73) were associated with remdesivir.…”

“…Cardiac arrest (adjusted odds ratio (aOR): 1.88, 95% confidence interval (CI): 1.08–3.29), bradycardia (aOR: 2.09, 95% CI: 1.24–3.53), and hypotension (aOR: 1.67, 95% CI: 1.03–2.73) were associated with remdesivir. In particular, from a total number of 2107 individual case safety reports, 93 out of 2107 patients (i.e., 4.41%) experienced cardiac arrest, 79 (3.75%) experienced bradycardia, 19 patients suffered from cardiogenic shock, 48 patients reported hypotension and about a hundred patients experienced electrophysiological conduction changes, including atrial fibrillation, ventricular tachycardia, and fibrillation, sinus tachycardia, QT prolongation, atrial flutter, torsade de points, and others [ 103 ].…”

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events

“…A recent article suggests that CV events are related to this drug. 3 The evidence comes from interrogation of the WHO global database of individual case safety reports (ICSRs) 4 to detect CV signals. The VigiBase incorporates the data of 20 million individuals from more than 130 countries.…”

Re: ‘ESCMID COVID-19 living guidelines: drug treatment and clinical management’ by Bartoletti et al

“…Because of the lack of a meaningful effect on mortality or disease progression, WHO guidelines recommend against the use of RDV[ 2 ]. Importantly, Bartoletti et al do not mention the severe cardiac side effects associated with RDV use that are now increasingly reported in international pharmacovigilance databases, including cardiac arrest, bradycardia, and hypotension[ 3 , 4 ]. Multiple case reports of bradycardia and other electrocardiogram changes have been reported in the literature following RDV administration[ 5 , 6 ].Mechanisms of RDV-induced cardiotoxicity are not elucidated but might include alterations in the adenosine metabolism[ 5 ] and in vitro data suggest a significant impact of RDV on cell viability of human pluripotent stem cell cardiomyocytes[ 3 ].…”

“…Importantly, Bartoletti et al do not mention the severe cardiac side effects associated with RDV use that are now increasingly reported in international pharmacovigilance databases, including cardiac arrest, bradycardia, and hypotension[ 3 , 4 ]. Multiple case reports of bradycardia and other electrocardiogram changes have been reported in the literature following RDV administration[ 5 , 6 ].Mechanisms of RDV-induced cardiotoxicity are not elucidated but might include alterations in the adenosine metabolism[ 5 ] and in vitro data suggest a significant impact of RDV on cell viability of human pluripotent stem cell cardiomyocytes[ 3 ]. The recommendation to use RDV in hospitalized COVID-19 patients should be performed after careful assessment of the benefit-risk balance which has clearly changed since the initial publication of the ACTT-1 trial.…”